Role of Innate Immunity in Pathogenesis of Chlamydia Pneumonia Infection

描述（由申请人提供）：肺炎衣原体是社区获得性肺炎的重要原因，也是过敏性气道疾病和哮喘恶化的重要原因。新的证据表明，Toll样受体（TLR）可能在宿主防御C。肺炎感染。我们的研究表明，MyD 88-/-小鼠无法产生早期炎症反应，未能从肺部清除细菌，并发展出延迟和持续的肺部炎症，导致与野生型小鼠相比死亡率增加，但野生型（MyD 88 +/+）同窝对照小鼠迅速从感染中恢复。这些结果表明，通过MyD 88的TLR信号传导是宿主防御C的重要组成部分。肺炎。而C.尽管在体外从骨髓来源的巨噬细胞和树突状细胞释放肺炎杆菌诱导的细胞因子是TLR 2依赖性的，但我们没有观察到TLR 2-/-和TLR 4-/-小鼠中细菌清除或肺部炎症消退的显著缺陷。这些观察结果表明，MyD 88对宿主防御C.肺炎，但也表明MyD 88-和/或TLR-非依赖性途径导致MyD 88-/-小鼠中的延迟和慢性肺部炎症。TLR/MyD 88-独立途径，包括NOD 1和NOD 2也可能参与先天性宿主防御这种专性细胞内生物。我们还观察到紫外线对C.肺炎感染使小鼠对变应原敏感，并加剧变应原介导的嗜酸性气道炎症，肺中有Th 2型应答。这些研究推动了我们将在这里提出的研究中进行批判性检验的假设，这些假设是围绕一个中心假设组织的：宿主对C的反应。肺炎克雷伯氏菌肺部感染和炎症是通过TLR 2/MyD 88途径介导的，该途径触发先天性和适应性免疫防御，而先天性和适应性免疫防御又在肺炎克雷伯氏菌的发病机制中起重要作用。肺炎感染和宿主反应，以清除肺部的细菌。所产生的初始炎症与强烈的细胞因子应答相关，以清除急性感染，包括IFN-γ，但也增强了变应原介导的致敏作用和嗜酸性粒细胞气道炎症以及通过促进肺中的Th 2偏向而由变应原激发引发的过敏性哮喘。具体目标是：1.研究TLR 2/TLR 4和MyD 88依赖性和非依赖性信号通路在宿主先天性和适应性抗C.肺炎克雷伯氏菌诱导的小鼠肺部感染和炎症的研究; 2.确定和比较造血和肺上皮细胞在肺炎克雷伯氏菌中的作用。肺炎衣原体诱导的免疫应答和肺部炎症3-确定肺炎衣原体感染对变应原介导的肺部嗜酸性气道炎症的发展的影响。意义：我们提出的研究将导致更好地理解先天性和适应性免疫反应在宿主防御C。肺炎克雷伯氏菌感染的分子机制，包括TLR/MyD 88通路和NOD 1/NOD 2受体的作用，以及C.肺炎杆菌感染加剧了过敏原介导的嗜酸性气道炎症，并可能为治疗和/或预防过敏性哮喘提供新的靶点。

DESCRIPTION (provided by applicant): Chlamydia pneumoniae is an important cause of community acquired pneumonia that also significantly contributes to allergic airway disease and exacerbation of asthma. Emerging evidence suggests that Toll-Like Receptors (TLRs) may play a role in host defenses against C. pneumoniae infection. Our studies show that MyD88-/- mice were unable to mount an early inflammatory response, failed to clear the bacteria from their lungs, and developed a delayed and sustained lung inflammation that led to increased mortality compared to wild type mice, but wild-type (MyD88+/+) littermate control mice rapidly recovered from infection. These results indicate that TLR signaling via MyD88 is an essential component of host defenses against C. pneumoniae. While C. pneumoniae -induced cytokine release in vitro from bone marrow derived macrophages and dendritic cells are TLR2-dependent, we did not observe a significant defect in bacterial clearance or resolution of lung inflammation in TLR2-/- and TLR4-/- mice. These observations suggest that MyD88 is critical to host defense against C. pneumoniae, but also indicate that MyD88- and/or TLR-independent pathways lead to the delayed and chronic lung inflammation in MyD88-/- mice. TLR/MyD88-independent pathways which include NOD1 and NOD2 may also be involved in innate host defenses against this obligate intracellular organism. We also observed that UV killed or live C. pneumoniae infection sensitizes the mice for allergens and exacerbates allergen-mediated eosinophilic airway inflammation with a Th2 type response in the lung. These studies have driven hypotheses that we will critically test in studies proposed here and that are organized around a central hypothesis: Host response to C. pneumoniae lung infection and inflammation is mediated through TLR2/MyD88 pathways that trigger innate and adaptive immune defenses which in turn play an important role in the pathogenesis of C. pneumoniae infection and host responses to clear the bacteria from the lungs. The resulting initial inflammation which is associated with intense cytokine responses to clear the acute infection, including IFN-y but also enhances allergen-mediated sensitization and eosinophilic airway inflammation and allergic asthma triggered by allergen challenge by promoting a Th2 bias in the lung. Specific Aims are: 1- To investigate the role of TLR2/TLR4 and MyD88-dependent and-independent signaling pathways in innate and adaptive host responses against C. pneumoniae- induced lung infection and inflammation in mice; 2- To determine and compare the roles of hematopoietic and lung epithelial cells in C. pneumoniae- induced immune responses and lung inflammation 3- To determine the impact of C, pneumoniae infection on the development of allergen-mediated eosinophilic airway inflammation of the lung. Significance: Our proposed studies will lead to improved understanding of the role of innate and adaptive immune responses in host defenses against C. pneumoniae infection, including the role of TLR/MyD88 pathway and NOD1/NOD2 receptors, as well as the molecular mechanisms by which C. pneumoniae infection exacerbates allergen- mediated eosinophilic airway inflammation, and may provide new targets for treatment and/or prevention of allergic asthma.